Pharmaceutical composition for ophthalmological and rhinological application

ABSTRACT

The invention concerns a pharmaceutical composition which contains at least panthenol and/or pantothenic acid and hyaluronic acid and/or hyaluronate and optionally additionally pharmaceutical auxiliary agents. The invention further concerns the use of the pharmaceutical composition for the treatment of ophthalmological and/or rhinological malfunctions.

The invention concerns a pharmaceutical composition and the use thereoffor the treatment of ophthalmological and rhinological malfunctions.

The “dry eye” syndrome is also referred to as the Sicca syndrome or alsoas the Sicca symptoms. The “dry eye” syndrome, the symptoms of whichinvolve inter alia burning, scratchiness, and a gritty feeling in theeye as well as blurred vision is to be attributed to functionaldisturbances in the tear film.

The “dry eye” syndrome can also be attributed to a reduced flow oftears, which can involve various pathological causes. The reduced flowof tears can result in the formation of only an inadequate or no tearfilm on the surface of the eye. The tear film acts inter alia as a slipor lubricating agent between the eyelid and the surface of the eye. As aresult of the absence of or inadequate tear film, the epithelial layerscan suffer from considerable trauma.

The cause of those functional disturbances is also for exampleenvironmental influences which give rise to allergies, such as forexample pollution or the effect of ozone. In particular ozone pollutionwhich rises in Summer months can not only give rise to a disturbance intear production but can also cause a disturbance in the physiologicaltear film. For example hyaluronic acid and proteins contained in naturaltear film are destroyed by the effect of ozone. It has further beenfound that the Sicca syndrome is frequently linked to a contact allergycaused by cosmetics on the eye.

It is known from Spektrum Augenheilkunde (1998) 3/4: 174-176 thathypoosmolar sodium hyaluronate drops can be used for therapy for the“dry eye” syndrome. In that case sodium hyaluronate of a molecularweight of 5,000,000 Daltons was used.

It is further known from Spektrum Augenheilkunde (1995) 9/5: 215-217that bacterially synthesised hyaluronate can be used for treating the“dry eye” syndrome. It is known from Jpn. J. Ophthalmol. (1996) 40:62-65 that the improvement in tear film stability is achieved by meansof sodium hyaluronate eye drops which contain at least 0.1% of sodiumhyaluronate.

It is known from Klinische Monatsblätter für Augenheilkunde (1996) 209;84-88 that dexpanthenol-bearing eye drops improve the cornea-epithelialbarrier function which is disturbed by virtue of an insufficient tearfilm.

The use of panthenol is further known for the treatment of cauterisationeffects, burns and ray damage to the skin as well as for the treatmentof inflammation of the eyes.

The object of the present invention is to provide a pharmaceuticalcomposition, which permits better therapy of diseases of the eye whichin particular involve functional disturbances to the tear film or areduced flow of tears.

A further object of the invention is to provide a pharmaceuticalcomposition which permits a treatment of dry mucous membrane of thenose.

That object is attained by the provision of a pharmaceutical compositionwhich includes at least panthenol and/or pantothenic acid and hyaluronicacid and/or hyaluronate and optionally additionally pharmaceuticalauxiliary agents.

The term “pharmaceutical auxiliary agents” is used to denote solvents,dissolving aids, dissolving accelerators, salt-forming agents, salts,buffer substances, viscosity- and consistency-influencing agents,gel-forming agents, emulsifiers, solubilisers, wetting agents, spreadingagents, antioxidants, preserving agents, filling and carrier substancesand so forth.

Panthenol, that is to say (R,S)-2,4-dihydroxy-N-(3-hydroxypropyl)-3,3-dimethylbutyramide, which isalso referred to as pantothenol or pantothenyl alcohol, is known as anepithelialisation agent for the skin. Panthenol is the alcoholic analogof pantothenic acid and by virtue of the intermediate conversion has thesame biological effectiveness as pantothenic acid.

It has been found that the pharmaceutical composition according to theinvention can be used both for the therapy of ophthalmologicalmalfunctions and also for the therapy of rhinological malfunctions.

The pharmaceutical composition is particularly well suited to thetreatment of dried-out, dry or chronically dry mucous membrane of thenose.

The mucous membrane of the nose can suffer from drying out for examplein air-conditioned spaces or vehicles or for example in excessively dryspaces and rooms which are overheated in winter. In an unnaturally dryenvironment the mucous membrane of the nose can no longer fulfil itstask of pre-moistening the inhaled air. The mucous membrane of the nosethen swells shut as when suffering from a head cold. Consequentlysecretion is no longer formed but dry crusts are formed, which easilyresult in bleeding cracks in the mucous membrane in the nose. Anosebleed can possibly also occur.

Drying-out of the mucous membrane of the nose is also promoted forexample by dust at the workplace or by pollutants such as cigarettesmoke, formaldehyde, sulphur oxides, nitrogen oxides and the so forth.In addition drying-out of the mucous membrane of the nose can also beattributed to nasal septum curvature or inflammation of the mucousmembrane during a cold or an allergy. Dry mucous membrane cells die off.In addition pathogens can pass into the body by way of the dried-outmucous membrane. Extreme cases can involve hole formation in the septumbecause the mucous membrane cells which have died off no longeradequately supply the cartilage tissue therebeneath.

Drying-out of the mucous membrane of the nose can also be due tomedicational influences such as for example on-going use ofswelling-reducing cold agents.

A dried-out mucous membrane of the nose can further result incomplaints, in particular when breathing, and thus troubles such as forexample difficulty in going to sleep or snoring while asleep.

The pharmaceutical composition according to the invention extremelyadvantageously has a dual effect. On the one hand hyaluronic acid or thesalts thereof have a high water binding capacity which counteracts orcounteract drying-out of the mucous membrane of the nose. On the otherhand panthenol and/or pantothenic acid provide for faster healing ofwounds when injuries have already occurred to the nasal mucous membrane,for example due to mechanical removal of the crusts formed, as forexample by ‘nose boring’.

The composition according to the invention is thus used in the case ofdrying-out of the mucous membrane of the nose, caused by environmentalfactors, and also in relation to pathologically induced drying-out ofthe nasal mucous membrane.

The simultaneous supply of moisture to the mucous membrane of the noseand the prevention of fast drying-out of the mucous membrane, and alsothe improved wound healing effect, give rise to a rapid reduction inswelling of the mucous membrane, reduced itching and a ‘clear nose’through which the person in question can breathe again.

The composition according to the invention results in fast healing andalleviation of the troubles in the case of people with dry and/ordried-out mucous membrane of the nose.

The pharmaceutical composition according to the invention can beparticularly advantageously used in the treatment of chronic rhinitis,rhinitis sicca, rhinitis sicca anterior and hybrid forms thereof.

The further information hereinafter is set forth essentially in relationto the ophthalmological use of the pharmaceutical application. Thisinformation however correspondingly applies to rhinological use. Forexample, in the case of a formulation for rhinological application, thesame forms of administration and the same compositions can be used.

The inventors of the present invention further surprisingly found that,with the simultaneous application of panthenol and/or pantothenic acidand hyaluronic acid and/or hyaluronate to the eye or on the surface ofthe eye, a synergistic effect occurs in regard to the treatment ofophthalmological diseases which are linked to functional disturbances ofthe tear film or an inadequately formed tear film.

In particular it has been found that accelerated epithelialisation of acornea damaged by virtue of an insufficient tear film occurs withtopical application of the pharmaceutical composition according to theinvention.

Preferably the pharmaceutical composition according to the invention isprepared, in the treatment of ophthalmological malfunctions, in the formof eye drops, eye solutions, eye lotions, eye sprays, eye ointments oreye tablets for topical application to the eye or the surface of theeye.

In the case of rhinological use the pharmaceutical composition ispreferably prepared in the form of nasal sprays, nose drops or noseointments.

To produce a nose or eye ointment the hyaluronic acid and/or hyaluronateand at least panthenol and/or pantothenic acid can be introduced forexample into a mixture of viscous paraffin and white Vaseline. Inaddition for example low-viscosity paraffin or wool wax can also be usedin ointments.

Preferably the pharmaceutical composition is prepared in the form of anose or eye spray or in the form of nose or eye drops. In that respectgenerally the hyaluronic acid and/or hyaluronate and the panthenoland/or pantothenic acid are dissolved in aqueous solutions.

In that respect, in accordance with a preferred embodiment forophthalmological use, the aqueous solutions are isotonic solutions, withrespect to the tear fluid. In the case of isotonic solutions osmolarityis approximately 300 mOsm/l. In accordance with a further preferredembodiment the pharmaceutical composition according to the invention ishypoosmolar. In that case osmolarity can be for example about 160-180mOsm/l. A hypoosmolar solution is used in particular when an abnormallyhigh level of osmolarity of a tear film in a patient with dry eyes hasto be compensated.

Sodium chloride, boric acid etc. are used for isotonisation of theaqueous solution. The pH-value of the aqueous solution is in a range ofpH 6 to 9, preferably pH 6.5 to 8.5, further preferably pH 7.4. Buffersolutions such as for example phosphate buffer, acetate buffer,acetate-borate buffer, citrate buffer and borate buffer are used toadjust the pH-value.

In the case of nose drops or nasal sprays for the treatment of dried-outor dry nasal mucous membrane the active substances, that is to saypantothenic acid and/or panthenol and hyaluronic acid and/orhyaluronate(s) are put in a suitable, preferably isotonic, medium.Preferably sorbitol is used for isotonisation purposes. It is howeveralso possible to use other media such as for example physiologicalsaline solution.

As discussed hereinbefore with reference to the rhinological applicationof the pharmaceutical composition, hyaluronic acid or hyaluronatesthereof has or have a high water binding capacity. That water bindingcapacity advantageously provides that the eye is supplied with moistureor drying-out of the eye is counteracted. In addition hyaluronic acid orhyaluronates thereof also acts or act as a viscosity regulator.

In the present case the term viscosity regulator is used to denotesubstances which are pharmacologically compatible and have aviscosity-increasing effect. Preferably the viscosity regulators whichcan be further used have a viscoelastic behaviour.

The viscosity-increasing effect extremely advantageously provides thatthe pharmaceutical composition applied to the surface of the eye or thenasal mucous membrane enjoys an increased residence time thereat anddoes not immediately flow away again from the surface of the eye or thenasal mucous membrane.

Besides the hyaluronic acid or hyaluronate it is additionally alsopossible to use chondroitin sulphate, polyacrylamide, polyacrylic acid,polyacrylic resins, polyethylene glycol, cellulose derivatives,polyvinyl alcohol, polyvinyl pyrrolidone or mixtures thereof asviscosity regulators.

In accordance with a preferred embodiment, besides hyaluronic acidand/or hyaluronate, no further viscosity regulator is used.

The hyaluronic acid or the hyaluronate can be isolated from the vitreoushumour of a bovine eye but also from cockscombs. In addition hyaluronicacid or hyaluronate can also be produced in bacterial strains inpharmaceutical quality.

For example potassium, sodium, calcium and/or magnesium hyaluronates canbe used as salts of hyaluronic acid.

The hyaluronate sodium hyaluronate is particularly preferred.

Hyaluronic acid is inter alia a constituent part of the vitreous humourof the eye and in that respect does not represent a compound which isforeign to the human organism. For that reason hyaluronic acid is verywell compatible, from the immunological point of view.

Extremely advantageously hyaluronic acid or hyaluronate enjoys astructural similarity with mucin. Mucin forms the lowermost layer of thethree-layer tear film and provides for optimum wetting of the cornea andconjunctiva epithelia.

Hyaluronic acid and/or hyaluronate thus imitates the mucous phase of thetear film and prolongs on the one hand the residence time on the eye andimproves wettability of the eye. Imitation of the mucous phase on theother hand also causes a reduction in friction between the eye and theeyelid and thus a marked reduction in mechanical irritation of the eye.

The use of hyaluronic acid or hyaluronates in the pharmaceuticalcomposition produced in accordance with the use of this invention isextremely advantageous in particular in terms of disturbance to wettingof the eye, that is to say in the case of what is referred to as “dryeye”, and for the treatment of epithelium lesions which result fromdisturbances to wetting of the eye.

Aqueous sodium hyaluronate solutions are fluids with non-Newtonian flowproperties. By virtue of that physical property, aqueous sodiumhyaluronate solutions are excellently well suited as slip andlubricating agents with a good cling effect and a prolonged residencetime on the conjunctival and corneal epithelia, without adverselyaffecting visual efficiency. A concentration of 0.1% by weight of sodiumhyaluronate in the composition according to the invention considerablyimproves the subjective feeling of the patients, which is important whentreating dry eyes.

The non-Newtonian flow behaviour of the hyaluronic acid provides aproperty which is excellent for use on the eye, namely that viscositydecreases with increasing shearing rate.

After application of the pharmaceutical composition according to theinvention to the cornea of the eye, a shearing stress is applied to thepharmaceutical composition by way of the blinking movement of theeyelid, whereby the initially increased viscosity is reduced. Theviscosity is reduced due to the blinking movement of the eyelid so thata uniform film is formed on the surface of the eye. After the blink theviscosity increases so that the film adheres firmly to the surface ofthe eye.

The non-Newtonian flow properties of the pharmaceutical compositionaccording to the invention, which are further produced by hyaluronicacid or hyaluronate in prepared solutions, gels, pastes or ointments,and the structural similarity thereof with mucin, besides an excellentslip and lubricating effect, also afford excellent adhesion to thecornea of the eye. Mechanical irritation of the eye which occurs withthe Sicca syndrome is greatly reduced or eliminated. In addition, thefact that adhesion of the pharmaceutical composition on the cornea ofthe eye is improved by virtue of the anti-Newtonian flow propertiesprovides for faster healing of epithelium lesions.

In addition sodium hyaluronate-bearing eye drops exhibit properties suchas to promote healing of wounds on the epithelia of the eye, in animaltesting. It was found that hyaluronic acid or sodium hyaluronate, independence on concentration, promoted the migration of epithelium cellsand thus wound healing. A 0.1% by weight sodium hyaluronate solutionimplemented increased epithelium cell migration in the case of corneaepithelium cells of rabbits.

Hyaluronic acid or sodium hyaluronate also caused faster and betterwound healing, that is to say which takes place with less scarring, inthe event of injury to the cornea epithelium or in the case ofcauterisation of the cornea.

The precise operative mechanism involved in the promotion of woundhealing by hyaluronic acid is still unexplained. While an influence onthe circulation of blood through the surrounding cells appears to beless probable, there are various pointers to an effect on cells whichplay a part in the inflammation process.

Finally, in dependence on dose, hyaluronic acid exhibits a protectiveaction in relation to damage to cells by oxygen radicals. Free oxygenradicals slow down the wound healing process and thus play a crucialrole in the inflammation situation.

The anti-inflammatory effect of hyaluronic acid or hyaluronate and theprotection afforded by hyaluronic acid or hyaluronate from the harmfuleffect of oxygen radicals co-operate in synergistic relationship withthe action of the panthenol or pantothenic acid in the pharmaceuticalcomposition in accordance with the invention.

In accordance with a further preferred embodiment the hyaluronic acidand/or hyaluronate are of a molecular weight which is in a range ofabout 50,000 to about 10,000,000 Daltons, preferably from about 250,000to about 5,000,000 Daltons. Particularly preferably the molecular weightof the hyaluronic acid or the hyaluronate is from 500,000 to 4,000,000Daltons. Very preferably the hyaluronic acid or the hyaluronate is of amolecular weight of about 1,500,000 to 3,500,000 Daltons.

The high molecular weight of the hyaluronic acid or the hyaluronate usedsuch as for example sodium hyaluronate provides for a high level ofviscoelasticity at a low level of concentration. The molecule chains arepresent in the solution in a random arrangement in a tangledconfiguration. Under the influence of the shearing forces exerted by themovement of the eyelid, the macromolecules are oriented in substantiallyparallel relationship. That change in the three-dimensional structureunder the influence of shearing forces is thought to be crucial for theexcellent viscoelastic properties.

Upon lid opening the substance covers over the surface of the corneaand, by virtue of the high water binding capacity of hyaluronate, alsorepresents protection against evaporation. That is advantageous both inrelation to the “dry eye” syndrome which involves a reduction in theamount of tear fluid in the eye, and also in the treatment of adried-out or dry nasal mucous membrane.

In accordance with a further preferred embodiment the amount ofhyaluronic acid and/or the amount of hyaluronate is about 0.005% byweight to about 5% by weight, preferably about 0.01% by weight to about1% by weight, in each case in relation to the total weight of thepharmaceutical composition.

Particularly preferably the amount of hyaluronic acid and/or the amountof hyaluronate is about 0.05% by weight to about 0.5% by weight, withrespect to the total weight of the pharmaceutical formulation.

Extremely advantageously hyaluronic acid and hyaluronates respectivelyhas or have the property of binding water. That property of bindingwater is particularly advantageous in regard to treatment of the Siccasyndrome as unwanted drying-out of the cornea of the eye iscounteracted. Levels of concentration of 0.1% by weight to 0.3% byweight with respect to the total weight of the pharmaceuticalformulation, hyaluronic acid and/or hyaluronate, have proven to behighly satisfactory.

A further diagnostic parameter in regard to diagnosis of the “dry eye”syndrome is the tear film tearing time which makes it possible toprovide information about the quality of the tear fluid. In that casefor example the tear film is dyed with fluorescein and the patient isthen asked to keep the eyes open as long as possible without a blinkreflex. A slit lamp is then used to establish when the tear film tearsopen for the first time. If the period of time is less than 10 seconds,there is the suspicion of the “dry eye” syndrome. In that respecthyaluronic acid at a concentration of 0.1% by weight to 0.3% by weighthas proven to be highly effective in regard to prolonging the tear filmtearing time.

The simultaneous action of panthenol and/or pantothenic acid and theprovision of an artificial tear film leads to a synergistic effect whichpermits faster therapy of epithelium lesions, in particular in the “dryeye” syndrome.

It has surprisingly been found that the joint application of panthenoland/or pantothenic acid and hyaluronic acid and/or hyaluronate leads torapid epithelialisation. At the same time extremely unpleasant itchingwhich occurs when epithelium lesions on the eye are involved is quicklyalleviated.

The pharmaceutical composition according to the invention is accordinglya drug combination.

It has been found that the hyaluronic acid and/or hyaluronate, by virtueof the non-Newtonian flow behaviour, have very suitable viscoelasticproperties for use on the surface of the eye. The non-Newtonian flowbehaviour delays the draining away of the pharmaceutical compositionapplied to the eye and thus prolongs the contact with the cornea of theeye. Accordingly the panthenol and/or pantothenic acid can be kept onthe cornea over a longer period of time, for example at least 30 minutesto at least 60 minutes.

Caused by the viscoelastic properties of hyaluronic acid or hyaluronate,the panthenol and/or pantothenic acid is readily distributed againsubstantially uniformly over the entire surface of the eye in eacheyelid blink, insofar as a certain draining-away effect should occur.

Extremely advantageously therefore the panthenol and/or pantothenic acidact uniformly on the surface of the eye over the entire duration of thetreatment. That can advantageously provide that, when conducting thetherapy, on the one hand the dosage of panthenol and/or pantothenic acidcan be reduced while on the other hand the duration of the treatment canbe shortened.

It is preferred if the amount of panthenol and/or pantothenic acid isabout 0.5% by weight to 10% by weight, preferably about 20% by weight to5% by weight, with respect to the total weight of the pharmaceuticalcomposition. An amount of about 3% by weight with respect to the totalweight of the pharmaceutical composition has proven to be highlysuitable.

In accordance with a preferred embodiment the panthenol is present inthe form ofD-(+)-2,4-dihydroxy-N-(3-hydroxypropyl)-3,5-dimethylbutyramide. Thatdextrorotatary D-configuration is also referred to as dexpanthenol.

In accordance with a further preferred embodiment of the invention thepantothenic acid is in the form of a water-soluble salt, preferablysodium pantothenate or calcium pantothenate.

Extremely advantageously dexpanthenol has water-binding properties. Thatadvantageously supplements the water-binding properties of hyaluronicacid and/or hyaluronate. In addition, the wound healing-promotingeffects of hyaluronic acid and/or hyaluronate and pantothenic acidand/or panthenol, in particular dexpanthenol, in dealing with epitheliumlesions of the corneal epithelium, supplement each other in a mannerwhich is not understood hitherto.

It is further preferred that the pharmaceutical composition is in theform of a solution, suspension, emulsion, gel, ointment, paste, powder,granules or a tablet which can preferably be used directly on the eye orapplied to the surface of the eye.

In accordance with a preferred embodiment the pharmaceutical compositionis in the form of a solution so that it can be applied for example inthe form of eye drops or an eye spray to the surface of the cornea ofthe eye.

It will be appreciated that it is possible for the pharmaceuticalcomposition according to the invention to be in the form of a solidwhich prior to application is firstly dissolved in an aqueous solutionsuch as for example a buffer solution. After dissolution of a solid, forexample in an aqueous buffer solution, that solution is subjected tosterile filtering and then applied to the cornea as an eye spray or eyedrops. Preferably, the solid and the solvent are already in sterile formwhen stored separately so that sterile filtration after production ofthe solution is not required. Thus, the user can apply thepharmaceutical composition directly after making up the mixture orsolution.

When preparing the pharmaceutical composition in the form of a solid,such as for example a powder, particles, granules or a tablet thepharmaceutical composition according to this invention preferablyincludes panthenol, pantothenic acid and/or salts of pantothenic acid,which can be readily dissolved in aqueous solutions, as well ashyaluronic acid which is very soluble in water and/or sodium hyaluronatewhich is very soluble in water.

Preferably the pharmaceutical composition according to the invention isin sterile form in single-dose or multi-dose receptacles.

Preferably for storage and delivery of a preserving agent-free,pharmaceutical composition in accordance with the invention, use is madeof the COMOD® system described in “PTA heute” 1996, No 12, pages1230-1232, which permits sterile storage and multiple delivery of thepharmaceutical composition according to the invention. It will beappreciated that it is also possible to use conventional single-dosecontainers which are thrown away after use.

For application of the pharmaceutical composition to the nasal mucousmembrane, it is possible to use for example the conventionally knownspray receptacles. For example it is possible to use the above-mentionedCOMOD® system. The 3K-system (3-Chamber system) described in DeutscheApotheker Zeitung 139, No 46, pages 48-51, 18th November 1999, has alsoproven to be very suitable. The pharmaceutical composition can also bedripped into the nose using a pipette.

When using hyaluronic acid and/or hyaluronate in the pharmaceuticalcomposition according to the invention the pharmaceutical composition ispreferably prepared free from preserving agent.

Preserving agents can damage the pre-corneal tear film and lead to areduction in the number of microvilli and microplicae of the surfacecornea epithelium cells. In particular the wide-spread benzalkoniumchloride has a great damage potential. In regard to the desired therapyof irritation of the eye induced by the Sicca syndrome, it isadvantageous to avoid any further irritation and/or damage to the eye bythe addition of preserving agents.

In principle the pharmaceutical composition according to the inventioncan also be introduced into the conjunctival sac in the form of eyetablets. The eye tablet quickly dissolves under the action of tearfluid.

However application of the pharmaceutical composition to the eye in theform of eye drops is preferred.

When preparing the pharmaceutical composition in the form of eyeointments or eye gels or ointments or gels for use in the nose, theactive substance are prepared for example in Vaseline or paraffin withand without the addition of emulsifier such as for example cholesterol,wool wax, wool wax alchohols, cetanol, and so forth.

The object of the invention is further attained by the use of apharmaceutical composition according to one of claims 1 to 8 for thetreatment of ophthalmological and/or rhinological malfunctions.

Preferably the pharmaceutical composition according to one of claims 1to 8 is used for the treatment of ophthalmological malfunctions whichare linked to disturbances to wetting of the cornea of the eye.

Further preferably the pharmaceutical composition is used for thetreatment of allergic rhinoconjunctivitis, atopic keratoconjunctivitis,allergic keratoconjunctivitis, gigantopapillary conjunctivitis,conjunctivitis vernalis, episcleritis such as for example episcleritisperiodica, episcleritis partialis fugax, scleritis, tenonitis, Sjögrensyndrome or hybrid forms thereof.

Preferably the pharmaceutical composition according to one of claims 1to 8 is used for the treatment of rhinological malfunctions which arelinked to drying-out phenomena in respect of the nasal mucous membrane.

Further preferably the pharmaceutical composition is used for thetreatment of chronic rhinitis, rhinitis sicca, rhinitis sicca anterioror hybrid forms thereof.

The pharmaceutical composition according to the invention can furtherextremely advantageously be used after operative interventions, forexample an operation on the septum of the nose. An application of thecomposition according to the invention prevents drying-out of the nasalmucous membrane and at the same time promotes re-epithelialisation ofthe nasal mucous membrane. The pharmaceutical composition according tothe invention can also be used after operative interventions on the eye.

As both the eye and also the nose are very important sense organs forthe human being, the pharmaceutical composition according to theinvention represents a significant advance in the field of ophthalmologyand rhinology.

EXAMPLE

Pharmaceutical Composition for Ophthalmological and RhinologicalApplication

-   50 mg/ml of dexpanthenol-   1.55 mg/ml of hyaluronic acid, molecular weight: 1.5×10⁶-3.5×10⁶    Daltons-   2 mg/ml of sodium citrate-   Addition of 1% aqueous citric acid solution until pH of 7.0-pH of    7.4 is reached-   Addition of water for injection purposes ad 1 ml

1. Use of panthenol and/or pantothenic acid and hyaluronic acid and/orhyaluronate and optionally additional pharmaceutical auxiliary agentsfor the production of a pharmaceutical composition for the treatment ofophthalmological and/or rhinological malfunctions.
 2. Use according toclaim 1 characterised in that the amount of hyaluronic acid and/or theamount of hyaluronate is about 0.005% by weight to about 5% by weight,preferably about 0.01% by weight to about 1% by weight, in each casewith respect to the total weight of the pharmaceutical composition. 3.Use according to claim 1 or claim 2 characterised in that the hyaluronicacid and/or the hyaluronate has a molecular weight which is in a rangeof about 50,000 to about 10,000,000 Daltons, preferably about 250,000 toabout 5,000,000 Daltons.
 4. Use according to one of claims 1 to 3characterised in that the hyaluronate is sodium hyaluronate.
 5. Useaccording to one of claims 1 to 4 characterised in that the amount ofpanthenol and/or pantothenic acid is about 0.5% by weight to 10% byweight, preferably about 2% by weight to 5% by weight with respect tothe total weight of the pharmaceutical composition.
 6. Use according toone of claims 1 to 5 characterised in that the panthenol is in the formof dexpanthenol.
 7. Use according to one of claims 1 to 5 characterisedin that the pantothenic acid is in the form of a water-soluble salt,preferably sodium pantothenate or calcium pantothenate.
 8. Use accordingto one of claims 1 to 7 characterised in that the pharmaceuticalcomposition is in the form of a solution, suspension, emulsion, gel,ointment, paste, powder, particles, granules or a tablet.
 9. Useaccording to one of claims 1 to 8 characterised in that theophthalmological malfunction is linked to disturbances to wetting of thecornea and conjunctiva of the eye.
 10. Use according to one of claims 1to 9 characterised in that the ophthalmological malfunction is selectedfrom the group consisting of allergic rhinoconjunctivitis, atopickeratoconjunctivitis, allergic keratoconjunctivitis, gigantopapillaryconjunctivitis, conjunctivitis vernalis, episcleritis, scleritis,tenonitis, Sjögren syndrome and hybrid forms thereof.
 11. Use accordingto one of claims 1 to 8 characterised in that the rhinologicalmalfunction is linked to drying-out phenomena of the nasal mucousmembrane.
 12. Use according to one of claims 1 to 8 or 11 characterisedin that the rhinological malfunction is selected from the group whichconsists of chronic rhinitis, rhinitis sicca and hybrid forms thereof.